Metal ions are essential for their diverse roles in biological processes but are lethal at high concentrations.1,2 The complex machinery of metal ion homeostasis (MH) maintains optimal cellular concentrations of metal ions and is critical for the survival of living organisms.2 In some pathogenic bacteria, the MH machinery confers antibiotic resistance, making it imperative to understand its mode of action. Metal ion sensing transcriptional regulators play the crucial role of controlling the expression of proteins that are involved in the uptake, transfer and efflux of metal ions in MH.2 The ArsR/SmtB family of metal ion sensing transcriptional repressor proteins provides heavy metal resistance in pathogenic prokaryotic organisms like Staphylococcus aureus, Mycobacterium tuberculosis, Listeria monocytogenes and Escherichia coli.2-4 These proteins have evolved from a common ancestry and are characterized by a helix-turn-helix fold. They function as transcriptional regulators by a mechanism of allosteric inhibition in which metal-ion binding or, alternatively, the formation of Cys-Cys disulfinde linkages triggers a conformational change that modulates their DNA-binding affinity. Understanding the mechanism of allosteric regulations and underlying changes in the structure and conformational dynamics of these proteins remains of fundamental interest. Effectively targeting this family of regulatory proteins would provide means to impair their heavy metal resistance and associated antibiotic resistance, potentially leading to novel therapeutic agents1,5 and can be extended to target similar metal sensor proteins such as CsoR, NikR and AdcR.